The present invention relates to substituted pyrrolidinone compounds, which are muscarinic acetylcholine receptor agonists and thus useful as nootropics and therapeutic agents for cerebral neural diseases; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.
Due to the increase in the number of the elderly population, the number of geriatric diseases such as dementia have increased dramatically. Senile dementia, as represented by Alzheimer""s disease, is a degenerative neural disease characterized by disorders of mental capacity including loss of memory, judgment and cognitive function. Patients suffering from Alzheimer""s disease show up to 90% degeneration of pre-synapse muscarinic acetylcholine neurons of the basal ganglia, which project into the frontal lobe and hippocampus, both of which manage learning, association, consolidation, and cognitive function such as perception in the cerebrum. However, the post-synapse muscarinic neurons in the forebrain and hippocampus are relatively unchanged. These facts suggest the strategy of medicinal development based on cholinergic deficiency hypothesis, which focuses on the stimulation of post-synapse receptors [See; R. T. Bartus, et al. Science, 217, 408-417 (1982)].
Tacrine is an acetylcholine esterase inhibitor that enhances available acetylcholine, which was developed as an agent involved in cognitive function. However, Tacrine had adverse effects. Recently, Aricept (donepezil, Eisai America, Inc., 1996), Exelon (rivastigmine, Novartis Pharmaceuticals Corporation, 2000) and Reminyl (galantamine hydrobromide, Janssen Research, 2001) having enhanced efficacy were developed [See; W. Greenlee, et al. I1 Farmaco, 2001, 56, 247-250]. However, oxotremorine, RS-86 and the like, which is a nonselective cholinergic agonist for directly stimulating cholinergic receptors, had adverse effects [See; R. Plate et al., Bioorg. Med. Chem., 2000, 8, 449-454].
Muscarinic Acetyl choline receptors exist in central and peripheral nervous systems in five subtype forms and play an important role in brain cognitive function. As the post-synapse muscarinic neuron in the forebrain and hippocampus is known to be relatively unchanging in patients suffering from Alzheimer""s disease, research on nootropics and therapeutic agents for Alzheimer""s disease focus on developing muscarinic agonists selective for the central nervous system and M1 receptor to decrease adverse effects and increase the efficacy of cholinergic drugs. Recently, muscarinic receptors in post- and pre-synapse of cholinergic nervous system, which is known to play an important role in learning and memorizing, is also found to regulate the process of forming amyloid precursor protein, which plays some role in precipitating beta-amyloid in patients suffering from Alzheimer""s disease. Further, muscarinic receptor agonist is known to accelerate secretion of soluble amyloid precursor protein and decrease phosphorylation of tau-protein. Accordingly, to develop nootropics and therapeutic agents for Alzheimer""s disease wherein beta-amyloid plaque and nerve fiber entanglement are accumulated, it is important to develop novel muscarinic receptor agonists of muscarinic acetylcholine receptor activity with high medicinal efficacy, low cholinergic adverse effects and selectivity for other receptors [See; C. C. Felder et al., J. Med. Chem. 2000, 43, 23, 4334-4353].
Already known muscarinic agonists active on the central nervous system include Talsaclidin (1997), YM-796 (1990), CI-1017 (2000), Xanomelin (1997), Milameline (1997), Sabcomeline (SB-202026, 1997), Alvameline (LU 25-109, 1997), AF-102 (1997), etc. [See; A. Fisher, Drug Dev. Res. 2000, 50, 291-297]. Additionally, a drug with pyrrolidine ring active on the nervous system includes an agent to ameliorate the condition of Alzheimer""s disease such as oxotremorine compounds [See; E. J. Trybulski et al., Bioorg. Med. Chem. Lett. 1992, 2, 827-832] and nootropics [See; D. Manetti et al., J. Med. Chem. 2000, 43, 1969-1974]. Further, although oxadiazole compounds of high affinity and excellent efficacy have been reported, they are known to have adverse effects. Recently, muscarinic agonists such as Pilocarpine (Salagen Tablets, MGI Pharma, Inc., 1998) and Cevimeline (AF102B, EVOXAC(trademark), SnowBrand Pharmaceuticals, Inc., 2000) were approved by FDA as a therapeutic agent for xerostomia originating from Sjogren""s syndrome, a sort of autoimmune disease affecting an exocrine gland [See; Drugs of the future, 2000, 25(6), 558-562]. The compound that has activity on muscarinic acetylcholine receptor is useful in pain, glaucoma, schizophrenia, anxiety, manic-depressive psychosis (circular insanity), bipolar psychosis, depression, somnipathy, epilepsy, cerebral ischemia, fecal incontinence and gastrointestinal mobility disorder [See; L. M. Merritt et al., U.S. Pat. No. 5,998,404].
However, some compounds active on muscarinic acetylcholine receptor have adverse effects such as hypersialosis, tears and gastrointestinal disorder. Accordingly, there is still a need to develop a novel compound that has muscarinic acetylcholine receptor activity, high efficacy and low cholinergic adverse effects.
Thus, the object of the present invention is to provide pyrrolidinone derivatives substituted with azacyclic isoxazole and azacyclic dihydroisoxazole compounds, which have high affinity for muscarinic acetylcholine receptor and thus useful as nootropics and therapeutic agents for neural diseases; and pharmaceutically acceptable salts thereof; processes for the preparation thereof; and pharmaceutical compositions comprising these compounds or salts.